The Proteomics and Mass Spectrometry Core Facility at the University of Massachusetts Medical School (UMMS) provides proteomics and metabolomics services for over 200 investigators at the UMMS and is responsible for maintaining a cutting-edge facility that enables our scientists to acquire molecular-level insights into a broad spectrum of biological and medical problems. To fulfill that responsibility, we request funds to upgrade our ThermoFisher LTQ linear ion trap mass spectrometry system to the LTQ Orbitrap ETD XL model and to purchase a Waters nanoAcquity UPLC system to be used as an integrated inlet for the spectrometer. The requested upgrade will provide access to high dynamic range (>3,000 within scan), high mass resolution (100,000) and high mass accuracy (<2 ppm) analyses required for several of our projects and to the electron transfer decomposition (ETD) technique absolutely required for other projects. The Waters nanoAcquity UPLC will substantially improve the performance of the LTQ Orbitrap by providing very high chromatographic efficiency and reproducibility through direct control of the spectrometer by the Thermo Xcalibur data system. This instrument will dramatically increase our ability to provide protein characterization and proteomics services to our major users group of 7 highly-productive NIH-funded investigators. It will also provide a broader range of analyses for other NIH-funded Facility users than is currently available with our Waters nanoAcquity UPLC-Q/TOF Premier instrument or other instruments in our facility. Projects that would be greatly enhanced by this instrument include in-depth proteome identification, identification of large MHC class II peptides, determination of protein conformation and contact points within protein complexes and aggregates through chemical cross-linking, site-specific measurement of protein folding dynamics by H/D exchange and protein population- based analysis of labile posttranslational modifications in mutant disease-causing proteins. Because there are no academic research instruments in central Massachusetts with the capabilities of the requested instrument, the purchase of this instrument will have a major impact on research at UMMS. PUBLIC HEALTH RELEVANCE: The research projects that will benefit from this instrument span a wide range of biological and biomedical areas: (1) the molecular basis of neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis;(2) the molecule basis for the immune response to viral diseases;(3) the role of glucose transport in diabetes;(4) the development of RNAi therapeutics;and (5) the molecular mechanisms of protein folding and how misfolding can lead to disease. This unique and powerful insights obtained will increase our understanding of the molecular basis for disease and, thereby, provide a rationale for the development of therapeutic treatments for a spectrum of human pathologies.